Nuclease‐independent functions of RAG1 direct distinct DNA damage responses in B cells
Abstract
Developing B cells generate DNA double‐stranded breaks (DSBs) to assemble immunoglobulin receptor (Ig) genes necessary for the expression of a mature B cell receptor. These physiologic DSBs are made by the RAG endonuclease, which is comprised of the RAG1 and RAG2 proteins. In pre‐B cells, RAG‐mediated DSBs activate the ATM kinase to coordinate canonical and non‐canonical DNA damage responses (DDR) that trigger DSB repair and B cell developmental signals, respectively. Whether this broad cellular response is distinctive to RAG DSBs is poorly understood. To delineate the factors that direct DDR signaling in B cells, we express a tetracycline‐inducible Cas9 nuclease in Rag1‐deficient pre‐B cells. Both RAG‐ and Cas9‐mediated DSBs at Ig genes activate canonical DDR. In contrast, RAG DSBs, but not Cas9 DSBs, induce the non‐canonical DDR‐dependent developmental program. This unique response to RAG DSBs is, in part, regulated by non‐core regions of RAG1. Thus, B cells trigger distinct cellular responses to RAG DSBs through unique properties of the RAG endonuclease that promotes activation of B cell developmental programs.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 16, 2022
- Source ID
- 10.15252/embr.202255429
Entities
People
- Abby M Green
- Brendan Mathias
- Haley A. Schmidt
- Jeffrey J Bednarski
- Lynn S White
- Nima Mosammaparast
- Rachel Johnston
- Stephanie J. Crowley
Organizations
- Alvin J. Siteman Cancer Center
- American Cancer Society
- American Society of Hematology
- Foundation for Barnes-Jewish Hospital
- Gabrielle’s Angel Foundation for Cancer Research
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- St. Louis Children's Hospital
- United States Department of Defense
- Washington University in St. Louis